Pharmacological Interventions in addiction Flashcards
Treatment gap for mental disorders?
Alcohol abuse/dependence has highest gap (<10% are treated)
SCZ has lowest gap
Overview of methods of pharmacotherapies for addictions
- substitution: give a drug to replace the abused one e.g. nicotine, opiates, BENZOS (diazepam/valium) for alcohol
- withdrawal: treat it
- abstinence: to prevent relapse
Role of alcohol with GABA receptor?
Drinking alcohol: activates GABA (inhibitory)
Regular drinking (not necessarily dependence): decreased GABA sensitivity]- alcohol tolerance
Role of alcohol with NMDA receptor?
Alcohol is a NMDA receptor antagonist -> reduced Ca2_ influx -> reduced excitation
ACUTE: NMDA inhibition
CHRONIC: receptor upregulation which is assoc w/ impaired memory
Molecular mechanisms of alcohol withdrawal?
- increased NMDA acitivity and L-type Ca channel -> Ca2+ influx -> hyperexcitability and cell death
- decreased GABA-benzo function and decreased Mg2+ inhibition via NMDA-r
Experimental evidence in the role of detoxes?
More detoxes assoc w/ less resposive treatment and heavier drinking
More detoxes assoc w/ cognitive impairment
Experimental evidence of glutamate and alcohol withdrawal?
(1)
MRS (Mag Res Spectroscopy)
day 1: increased glutamate
day 14: glutamate levels reduced closer to healthy controls
(2)
Acamprosate reduces MRS glutamate
Overview of treatment regimens for alcohol detox?
- Benzos are efficacious in reducing symptoms and signs of withdrawal and are treatment of choice
- -> no particular one (but consider kinetics e.g. lorazepam for liver failure
- -> some centres add acamprosate for anti-glutamate action
- carbamazpeine (glutamatergic anticonvuls) shown to be efficacious as an alternative to benzos]- mainly in other parts of world
Importance of vitamin supplementation in alcoholism?
- most alcohol dependent are vitamin deficient
- thiamine (B1) is key
- -> involved in brain metab
- -> adds to already toxic increased glutamate where brain cells are at risk of excitability (seizures)/death
Outcomes of vitamin deficiency?
Wernicke's Encephalopathy - opthalmopleiga (nystagmus) - ataxia - acute confusion [but these only present in 10% of pts, so must be alert] ---> fatal in 20%; medical emergency
[can detriorate to]
Korsakoff’s Syndrome
- irreversible short-term mem loss in presence of “normal” other cogn performance
Specifics of thiamine administration?
- IV/IM]- due to poor diet and aborption
DA relation to increase in substance use over time
EXPERIMENTAL USE
- low levels of DRD2 assoc w/ drug liking and impulsivity
- increase DA in substances of abuse
INCREASE -> DEPENDENCE
- low DRD2 levels seen in stim & alc addicts]- higher DRD3 in stim addicts, but not change for alc
- DA release is blunted or non-existent
- can get “high” without detectable increase in DA
DA and pharmacotherapy for addiction?
Block DA-ergic function to prevent high
- D2 antag: antipsych (atypical/typical)
Boost DA-ergic function to reduce dysphoria/irritability
- DA agonists (bromocryptine, disulfiram, methylphenidate, substitute e.g. with amphetaine, bupropion (DAT reuptake block), DRD3 antag (presynaptic- negative fdbk)
Mechanisms of alcohol metabolismt?
Alcohol -alc dehydrogenase-> acetaldehyde -aldehyde dehydrogenase ALDH-> acetate
Acetaldehyde build up causes nausea/flushing/headache/vomiting/palpitations/hypotension
How to target alcohol metabolism?
Disulfiram (200mg) inhibits aldehyde dehydrogenase
Contraind: psychosis/severe liver or cardiac path/epilepsy
Non-targeted effects of disulfiram
Dopamine B hydroxylase is the same family of aldehyde dehydrogenase
DA -DA-B-Hydroxylase-> NA
Disulfiram inhibits DA-B-Hydx too -> increase DA and less NA -> anxiety/mania/psychosis/depression
How to target GABA in alcohol dependence?
PHYSIOLOGY
GABA inhibits DA neurons which act on NAcc
μ-opiate-R are inhibitory for GABA -> increase DA firing
PHARMACOLOGY
- Baclofen is an agonist for GABA-B-r: shown to improve abstinence rates in alcohol dependence
- Tiagabine, vigabatrin, gabapentin, topiramate increase GABA levels and induce a similar effect
- opiate antag e.g. naltrexone block μ-opiate-R -> increased GABA -> reduced DA activity
(E) of baclofen?
(E)- Xi & Stein
Reduces alc self-administration]- baclofen mainly use for alcohol
Same seen for heroin and cocaine self administration
Relevance of naltrexone (ACTION ON BODY; EFFECT ON PT; MEDICAL USE)?
[opiate antag]
ACTION ON BODY
decreases pleasurable effects of alcohol (reduces impulsivity and modulates stress response too)
EFFECT ON PT
- reduces relapse rates to heavy drinking
USE OF NALTREXONE
- start after detox at 50mg od
- no opioid analgesia
- can “safely” drink]- can reduce drinking when started whilst drinking
- NICE: oral for 6 months; stop if drinking alc for 4-6 weeks
Types of opiate receptor and their action
μ: the pleasant feeling
kappa: the negative/depressive feeling
μ and kappa opioid receptor over stages of alcohol use (acquisition/abstinence/relapse)
ACQUISITION
high μ
low(er) kappa
ABSTINENCE/WITHDRAWAL
no μ
low kappa
RELAPSE
low μ
high kappa
Relevance of nalmefene (ACTION/EFFECT/USE)?
ACTION
decreases pleasurable effects of alcohol
EFFECT
reduces drinking
USE
- alc dependence (high drinking, psychosocial treatment and still drinking a lot); less severe dependence (doesnt need dtex)
- start when drinking (18g) as eeded
- S/E: nausea, insomnia]- severe
- no opioid analgesia
- recommended by NICE
Molecular features of acamprosate and its effects?
Taurine derivative
Unclear pharmacology, but reduces NMDA activity
- partial agonsit at modulatory site (via AMPA and mGLUR5)
-> increases abstinence rates and decreases relapses
How to decide which medication to give?
Starting post-detox
- support abstinence: acaprosate + disulfiram
- reduce relapse risk in “samplers”: naltrexone
- support abstinency for those w/ prominent anxiety: baclofen
Start whilst drinking to reduce drinking:
- Nalmefene (naltrexone)
How to “substitute” for heroin use?
Methadone
- blocks “on top” heroin use
- longer half life
- when in brain, heroin has less effect (as receptor blockage)
Types of opiates in pharmacotherapy?
Full Agonist
morphine, methadone
——–potentially lethal dose cutoff——–
Partial Agonist
buprenorphin
Antagonist
naltrexone
NB: naloxone must be available in the event of an opiate OD
Buprenorphin mechanism of action?
- High affinity for receptor, stopping “on top” heroin use]- so heroin has no effect on top
- long half life -> prolonged cover
OPIATES: Antagonist concept overview
- no intrinsic activity, just blocks receptor to deny access for other drug
BUT
- no reinforcement, so poor compliance
- precipitate withdrawal
OPIATES: Partial agonist concept overview
max effect: background stimulation of buprenorphine i.e. severely reduced
Opiate maintenance treatment overview?
Methadone:
- full agonist
- risk of fatal resp depress
- block effects of “on top” heroin
Buprenorphine
- partial μ-agonist and kappa antag
- no/less risk of fatal resp depres
- block “on top” heroin effects
- less dysphoria/feel more normal
Naltrexone]- for relapse prevention
- non-selective antag
Opiate withdrawal symptoms?
Altered function in locus coeruleus (NA storm)
- mydriasis, tachycardia, piloerection, restlessness
- diarrhoea, sweating, rhinorrhoea
- dysphora, insomnia, shivering
YOU DON’T NEED TO GIVE OPIATES TO TREAT OPIATE WITHDRAWAL
Relevance of opiate maintenance treatment?
- [reduce neurobiology of addiction]
- stops street use and reduces crime
- reduces IV risks
- keep in healthcare (psychosocial treatment)
- easier withdrawal when ready (flexible dosing)
Neurobiological basis of opiate withdrawal in locus coeruleus
Baseline: normal NA production
Acute opioid use: abnormally low NA production
Chronic opioid use: increased converting enzyme activity -> normal NA level
Discontinuing opioid use: increase cAMP (due to loss of inhibition) -> NA excessively high
Pharmacology of nicotine addiction
Nicotine replacement aids substitution, withdrawal and abstinence (i.e. relapse prevention): varenicline (partial nicotinic agonsit)
Bupropion (DA/NAergic) used for relapse prevention
NB: this must be done in addition to psychosocial smoking cessation therapies
